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PDBsum entry 4rj4
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Transferase/transferase inhibitor
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PDB id
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4rj4
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References listed in PDB file
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Key reference
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Title
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Discovery of selective and noncovalent diaminopyrimidine-Based inhibitors of epidermal growth factor receptor containing the t790m resistance mutation.
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Authors
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E.J.Hanan,
C.Eigenbrot,
M.C.Bryan,
D.J.Burdick,
B.K.Chan,
Y.Chen,
J.Dotson,
R.A.Heald,
P.S.Jackson,
H.La,
M.D.Lainchbury,
S.Malek,
H.E.Purkey,
G.Schaefer,
S.Schmidt,
E.M.Seward,
S.Sideris,
C.Tam,
S.Wang,
S.K.Yeap,
I.Yen,
J.Yin,
C.Yu,
I.Zilberleyb,
T.P.Heffron.
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Ref.
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J Med Chem, 2014,
57,
10176-10191.
[DOI no: ]
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PubMed id
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Abstract
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Activating mutations within the epidermal growth factor receptor (EGFR) kinase
domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell
proliferation and survival and are correlated with impressive responses to the
EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients.
Approximately 60% of acquired resistance to these agents is driven by a single
secondary mutation within the EGFR kinase domain, specifically substitution of
the gatekeeper residue threonine-790 with methionine (T790M). Due to
dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR),
we sought inhibitors of T790M-containing EGFR mutants with selectivity over
wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors
into selective EGFR inhibitors. X-ray crystal structures revealed two distinct
binding modes and enabled the design of a selective series of novel
diaminopyrimidine-based inhibitors with good potency against T790M-containing
mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and
desirable physicochemical properties.
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